Journal of Crohn's and Colitis, 2016, 607–618 doi:10.1093/ecco-jcc/jjw004 Advance Access publication January 7, 2016 Original Article

Original Article

Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis Vipul Jairath,a,b,c Guangyong Zou,b,d Claire E. Parker,b,e John K. Macdonald,b,e Mahmoud H. Mosli,b,e,f Reena Khanna,b,e Lisa M. Shackelton,b Margaret K. Vandervoort,b Turki AlAmeel,g Mohammad Al Beshir,g Majid AlMadi,h Talal Al-Taweel,i Nathan S. S. Atkinson,a Sujata Biswas,a Thomas P. Chapman,a Parambir S. Dulai,b,j Mark A. Glaire,k Daniel Hoekman,l Andreas Koutsoumpas,a Elizabeth Minas,m Mark A. Samaan,n Simon Travis,a Geert D’Haens,b,l Barrett G. Levesque,b,j William J. Sandborn,b,j Brian G. Feagan,b,c,e Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK bRobarts Research Institute, University of Western Ontario, London, ON, Canada cDepartment of Medicine, University of Western Ontario, London, ON, Canada dDepartment of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada e Department of Medicine, University of Western Ontario, London, ON, Canada fDepartment of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia gDepartment of Medicine, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia hDivision of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia iHaya AlHabeeb Gastroenterology Center, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait jDivision of Gastroenterology, University of California San Diego, La Jolla, CA, USA kDivision of Medical Sciences, University of Oxford, Oxford, UK lDepartment of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands mDepartment of Geratology, Oxford University Hospitals NHS Trust, Oxford, UK nDepartment of Gastroenterology, Guy’s and St Thomas’ Hospital NHS Trust, London, UK a

Corresponding author: Dr Vipul Jairath, DPhil, MRCP, Nuffield Department of Medicine, Oxford Clinical Trials and Research Unit, University of Oxford, Oxford, UK. Tel: 519-685-8500 (ext 35033); fax: 519-663-3658; Email: [email protected]

Abstract Background and Aims: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. Methods:  MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. Results:  In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]

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with more active disease confirmed by endoscopy [endoscopy subscore ≥  2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. Conclusions:  Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials. Keywords:  RCT, randomised controlled trial; DAI, Disease Activity Index; UC, ulcerative colitis; MCS, Mayo Clinic Score

1. Introduction Over the past 60 years, the randomised controlled trial [RCT] has undergone continuous evolution and refinement as a gold standard for evaluating the efficacy of new treatments. An increased understanding of the placebo response has been an integral part of this process. Determinants of the placebo response include natural variation in underlying disease, regression towards the mean, and the ‘true’ placebo effect 1 which is likely attributable to interrelated environmental and psychosocial factors.2 In clinical trials, these factors include patient expectations of treatment benefits, the response to observation and assessment [Hawthorne effect], the response to administration of a therapeutic ritual, the patient-physician relationship, and intrinsic features of trial design. 3,4 In the context of drug development, minimising the placebo response optimises the capacity to detect differences between active drug and placebo [assay sensitivity] and allows for the conduct of more efficient trials. Thus, identification of determinants of the placebo response is critical to trial design. Randomised controlled trials in ulcerative colitis [UC] have shown heterogeneous and often large placebo response rates that may have prevented identification of effective therapies. A  previous meta-analysis conducted by Su and colleagues identified several design features that influenced the placebo response.5 However, this study was conducted over a decade ago, before the modern-day era of biological therapies for inflammatory bowel disease, and included many trials that used outcome measures that are no longer considered appropriate. Identifying trial design criteria capable of consistently yielding predictable and low placebo rates increases the potential for more efficient trials. Based on these considerations, we conducted a meta-analysis to estimate placebo response and remission rates in both induction and maintenance phases of UC trials that included endoscopic evaluation of disease activity, using either the Disease Activity Index 6 or the nearly identical Mayo Score 7 for enrolment and outcome assessment. A meta-regression was conducted to identify trial design features that affected the placebo response.

2. Methods 2.1.  Data sources We searched MEDLINE [1948-April  2014], EMBASE [1947 May  2014], the Cochrane Central Register of Controlled Trials [2014], and the Cochrane Inflammatory Bowel Disease/Functional Bowel Disorders review group specialised trials register, without language restriction from inception to May 2014. The search strategies are reported in Table S1, available as Supplementary data at ECCOJCC online. Citations and abstracts for potentially relevant studies were selected and screened, and complete manuscripts were retrieved for assessment of eligibility. Abstracts from conference proceedings

[Digestive Disease Week and United European Gastroenterology Week; 2012–2014] and bibliographies of relevant studies, review articles, and meta-analyses were hand-searched to identify additional studies.

2.2.  Study selection Eligible studies were RCTs fulfilling the following criteria: [1] a placebo-controlled trial in adult patients with UC of either a biological agent, corticosteroid, immunosuppressant, or aminosalicylate; [2] use of the Disease Activity Index 6 or the nearly identical Mayo [or modified Mayo] Clinic Score 7,8 as enrolment criteria and for the assessment of clinical response and/or remission; [3] duration of at least 2 weeks for induction, and 4 months for maintenance of remission trials. Trials of probiotics, antibiotics, complementary therapies, or devices were excluded as were trials of hospitalised patients with severe UC. The Mayo Clinic score 7 and the Disease Activity Index 6 are 12-point scales incorporating four components of disease activity: stool frequency, rectal bleeding, mucosal appearance of the sigmoid colon on sigmoidoscopy, and physician’s global assessment. Although slight differences exist in the definitions used in these two instruments, they are sufficiently similar to be considered equivalent. Trials using modifications of the Mayo score [eg Modified Mayo Disease Activity Index] were also eligible for inclusion. We refer to either score collectively as the Ulcerative Colitis Disease Activity Index [UCDAI] in this paper.

2.3.  Data extraction and quality assessment Articles were independently assessed by pairs of investigators using pre-defined eligibility criteria. Disagreement between investigators was resolved by consensus. All data were extracted independently in duplicate into a Microsoft Excel spreadsheet [XP professional edition; Microsoft Corp., Redmond, WA, USA]. Outcomes extracted included the proportion of patients with clinical response and remission, corticosteroid- free remission, mucosal healing, and histological remission, when available. Additional features extracted were: [a] trial design and participant characteristics (number of treatment arms, trial development phase, year of publication, study location[s], first author nationality, number of participants, study duration, number of follow-up visits, frequency of follow-up visits, number of participants analysed, percentage of post- randomisation drop-outs, age, gender ratio); [b] type of intervention [drug class, concomitant therapy, dose, route of administration, frequency of administration, ratio of active drug to placebo]; [c] criteria for enrolment and outcome assessment [minimum UCDAI score for inclusion; UCDAI-based definitions of response and remission]; [d] disease severity and duration [baseline C-reactive protein [CRP] and calprotectin, disease distribution, and disease duration].

Placebo Rates in Ulcerative Colitis Trials The Cochrane Collaboration risk of bias tool was used to assess the methodological quality of the studies included.18 Two independent investigators assessed the risk of bias and disagreements were resolved by discussion.

2.4.  Data synthesis and analysis Placebo response and remission rates were pooled, overall and separately, for induction and maintenance phases of trials, using a random-effects model for rates on the logit scale. These were pooled separately to reflect the two common methods of trial design. A random-effects model was chosen to account for both between- and within-study variability. Point estimates and associated 95% confidence intervals [CIs] were converted back to the original scale. Mixed-effects meta-regression analyses with logits of event rates as outcome variables were used to assess the effect of each study-level characteristic on placebo rates.9 Clinical judgement and previously identified predictors of placebo response were used to establish factors for inclusion in the meta-regression.10 A  multivariable metaregression analysis was not performed due to the limited number of studies and co-linearity between study-level characteristics. Potential sources of clinical heterogeneity were evaluated by constructing stratum-specific rates of placebo response and remission for various patient and trial-level covariates. Statistical heterogeneity within these strata was quantified using I2 and Q-test statistics.5,11 A value below 50% represents lower levels of heterogeneity.12 Potential publication bias related to placebo rates9,13,14 was examined using funnel plots constructed by plotting the log odds ratio against the standard error, to emphasise differences between studies of smaller size within which biases are most likely to operate. Cumulative meta-analysis was also conducted by date of publication in order to provide an assessment of pooled placebo rates over time.15 Cumulative meta-analysis and its graphical representation were calculated and interpreted using a Bayesian approach whereby the next study continually updates the previous distribution, such that the last posterior distribution becomes the next prior distribution. All analyses were performed using Metafor package16 for R version 3.1.1.17

3. Results 3.1.  Search results The search yielded 7588 citations of which 3605 were duplicates and removed [Figure S1, available as Supplementary data at ECCOJCC online]. Of the remaining 3983 records screened, 227 full-text articles were selected and reviewed for eligibility. Of these, 77 articles reported 51 trials eligible for data extraction, including 48 induction and 9 maintenance phase studies. For the 48 induction phase6,78,19–60 trials containing 3043 participants randomised to placebo, response rates were evaluable in 43 trials and remission rates in 40 trials. For the 9 maintenance phase trials 8,20,26,50,55,61,62,63 containing 1019 participants randomised to placebo [range 34–260], response rates were evaluable in 5 trials and remission rates in 8 trials. Given the small number of maintenance trials, meta-regression to identify factors modulating the placebo response was only feasible for induction trials.

3.2.  Description of included studies Study characteristics and definitions used for response or remission are shown in Table S2, available as Supplementary data at ECCOJCC online. For induction trials, the mean age of participants

609 enrolled was 40.8 years [range 30–50 years], mean placebo sample size was 66 [range 5–331], and the number of centres ranged from 1 to 217. Length of follow-up ranged from 2 to 24 weeks. The majority of induction studies were designed as stand-alone [70%], phase 3 [63%], multicentre/multinational [65%], biological therapy [47%] trials with a first author from a North American centre [56%]. For maintenance trials, the mean age of participants was 40.6 years [range 37.3–46 years], the mean placebo sample size was 113 [range 34–260], the number of centres ranged from 9 to 251 and the majority investigated biological therapies [6/10; 60%]. Length of follow-up ranged from 12 to 96 weeks.

3.3.  Pooled placebo remission and response rates for induction and maintenance trials For induction trials, the pooled placebo remission rate was 10% [95% CI 7-13%; range 1–49%] and the pooled placebo response rate was 33% [95% CI 28-38%; range 6–92%]. Significant heterogeneity was observed among trials [I2  =  78.3%, p  8 weeks], date of publication [before 2005 vs after 2005], composite UCDAI score for trial eligibility [≥ 6 vs 6 weeks vs < 6 weeks] [Tables 1 and 2].

3.5.  Determinants of placebo response rate in induction trials

3.5.2.  Trial design and setting A higher pooled placebo response rate was observed in multicentre multinational induction trials compared with multicentre singlecountry induction trials [35% vs 26%, respectively; OR 1.59, 95% CI 1.01-2.51, p = 0.047] [Tables 1 and 2]. No significant differences in placebo response rates were observed between integrated induction/ maintenance trials compared with stand-alone induction trials [30% vs 35%; OR 0.75, 95% CI 0.48-1.16, p  =  0.193], induction trials published before or after 2005 [33% for both time periods; OR 0.99, 95% CI 0.65-1.50, p = 0.947], or according to number of follow-up visits [OR 1.05, 95% CI 0.94-1.17 per visit increment], or duration of follow-up [OR 1.02, 95% CI 0.97-1.06 per 1-week increment].

3.5.1.  Participant and disease-related characteristics Disease duration > 5 years before enrolment was associated with a significantly lower placebo response rate compared with disease duration < 5 years [33% vs 47%, respectively; OR 0.54, 95% CI 0.32-0.92, p = 0.020] [Tables 1 and 2]. Studies using an endoscopy subscore ≥ 1 for study entry were associated with a higher placebo response rate compared with studies using a more stringent entry criterion of endoscopy subscore ≥ 2 [46% vs 34%; OR 1.65, 95% CI 0.93-2.94, p = 0.086]. No differences were observed for the pooled placebo response rates according to requirement for

Placebo Rates in Ulcerative Colitis Trials

611 Response (95% CI)

Study Leiper, 2011 Feagan, 2013 Feagan, 2005 Feagan, 2000 Reinisch, 2011 van Assche, 2006 Probert, 2003 Sandborn, 2012 Rutgeerts, 2005 Rutgeerts, 2005 Rutgeerts, 2013 Rutgeerts, 2013 Vermeire, 2014 Mayer, 2014 Sands, 2012 Danese, 2014 Vermeire, 2011 Sandborn, 2014 Kamm, 2007 Lichtenstein, 2007 Marteau, 2005 Scherl, 2009 Sninsky, 1991 Schroeder, 1987 Sutherland, 1987 Sutherland, 1987 Sutherland, 1990 Beeken, 1997 Travis, 2014 Feagan, 2013 Sandborn, 2012 Lewis, 2008 Schreiber, 2007 van Deventer, 2006 van Deventer, 2004 Sandborn, 1994 Nikolaus, 2003 Ogata, 2006 Ogata, 2012 Sandborn, 2012 Sandborn, 2012 Sandborn, 2003 Steinhart, 1996

0.12 (0.02, 0.54) 0.26 (0.19, 0.33) 0.33 (0.03, 0.46) 0.25 (0.06, 0.62) 0.45 (0.36, 0.53) 0.45 (0.32, 0.58) 0.55 (0.34, 0.75) 0.35 (0.29, 0.41) 0.37 (0.29, 0.46) 0.29 (0.22, 0.38) 0.80 (0.31, 0.97) 0.80 (0.30, 0.97) 0.28 (0.17, 0.43) 0.35 (0.24, 0.49) 0.65 (0.51, 0.77) 0.33 (0.22, 0.46) 0.15 (0.05, 0.38) 0.30 (0.26, 0.35) 0.40 (0.30, 0.50) 0.26 (0.18, 0.36) 0.63 (0.55, 0.79) 0.40 (0.30, 0.52) 0.06 (0.02, 0.16) 0.13 (0.06, 0.28) 0.29 (0.20, 0.40) 0.20 (0.09, 0.38) 0.23 (0.13, 0.37) 0.92 (0.61, 0.99) 0.23 (0.17, 0.32) 0.40 (0.33, 0.49) 0.23 (0.17, 0.32) 0.23 (0.13, 0.36) 0.35 (0.25, 0.48) 0.41 (0.23, 0.62) 0.25 (0.06, 0.62) 0.40 (0.21, 0.63) 0.14 (0.02, 0.58) 0.10 (0.02, 0.31) 0.13 (0.05, 0.31) 0.29 (0.22, 0.37) 0.42 (0.29, 0.56) 0.36 (0.20, 0.55) 0.47 (0.27, 0.69)

RE Model

0.33 (0.28, 0.38)

0.00

0.20

0.40

0.60

0.80

1.00

Response

3.5.3.  Class of drug Pooled placebo response rates according to class of drug ranged from 19% to 36% [Table  1]. The lowest placebo response rate [19%; 95% CI 7-43%; I2 = 0.037] was observed for trials of immunosuppressants, whereas the highest placebo response rate [36%; 95% CI 31-40%; I2 < 0.001] was observed for trials of biological drugs. Trials of orally administered agents had the lowest placebo response rate [28%; OR 0.66, 95% CI 0.33-1.03] compared with trials of topically administered agents which had the highest placebo response rate [39%; 95% CI 27-53%; p = 0.065 for the comparison]. A randomisation ratio of active drug to placebo of > 1 had no impact on the placebo response rate [OR 1.01, 95% CI 0.68-1.50, p = 0.97] although the limited number of studies using asymmetrical allocation limited our ability to detect such an effect.

3.6. Time trends in the placebo rates Cumulative meta-analysis demonstrated a consistent increase in the placebo remission rate from 1987 to 2007 [from 5% to 14%] and remained constant [12% to 14%] through 2014 [Supplementary Figure  2, available as Supplementary data at ECCO-JCC online ]. Placebo response rates increased from 1987 to 2007 [from 13% to 33%], after which these rates remained constant [32% to 34% through 2014] [Supplementary Figure 3, available as Supplementary data at ECCO-JCC online, ].

3.7.  Sources of heterogeneity and risk of bias Heterogeneity among strata of relevant study features was slightly less evident in studies that were single-centre, used an integrated induction and maintenance trial design, evaluated

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612 Study

Remission (95% Cl)

Feagan, 2013

0.16 (0.10, 0.23)

Rutgeerts, 2005

0.17 (0.11, 0.24)

Rutgeerts, 2005

0.11 (0.06, 0.17)

Sandborn, 2014

0.15 (0.11, 0.22)

Hanauer, 2000

0.09 (0.03, 0.24)

Lichtenstein, 2010

0.58 (0.48, 0.68)

Oren, 1996

0.27 (0.15, 0.43)

Sandborn, 2012

0.14 (0.07, 0.24)

RE Model

0.19 (0.11, 0.30)

0.00

0.20

0.40 0.60 Remission

Study

0.80

Response (95% Cl)

Feagan, 2013

0.16 (0.10, 0.23)

Rutgeerts, 2005

0.20 (0.14, 0.28)

Rutgeerts, 2005

0.26 (0.19, 0.34)

Sandborn, 2014

0.31 (0.24, 0.38)

Sandborn, 2012

0.17 (0.09, 0.28)

RE Model

0.22 (0.17, 0.28) 0.00

0.10

0.20

0.30

0.40

Response Figure 1.  a. Forest plot of pooled placebo remission rates for induction trials. B. Forest plot of pooled placebo response rates for induction trials. c. Forest plot of pooled placebo remission rates for maintenance trials. d. Forest plot of pooled placebo response rates for maintenance trials.

an immunosuppressant or subcutaneously administered drug, enrolled patients with disease duration ≤ 5  years, and followed patients for > 8 weeks [Table  1]. Risk of bias for induction

studies was assessed as low or unclear for most parameters studied [Supplementary Table  3, available as Supplementary data at ECCO-JCC online].

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613

Table 1.  Stratum-specific placebo rates in induction trials. Response Trials N

Remission Pooled rate % [95% CI]

All trials 43 33 [29-37] Setting Multicentre, single country 14 26 [18-35] Multicentre, multinational 29 36 [31-41] Single-centre 3 22 [8-45] Design Stand-alone induction 35 35 [29-40] Induction and maintenance 10 30 [26-35] First author country North America 25 32 [27-37] Europe 17 38 [31-46] Other 2 12 [5-24] Drug class Corticosteroid 2 23 [19-29] Aminosalicylate 13 32 [20-47] Immunosuppressant 4 19 [7-43] Biological 22 36 [31-40] Other 5 34 [25-44] Route of administration Topical 9 39 [27-53] Oral 17 28 [22-34] Intravenous 13 37 [29-45] Subcutaneous 7 35 [29-41] Disease severity on entry Mild-moderate 21 32 [25-39] Moderate-severe 24 34 [29-40] Disease duration on entry ≤ 5 years 6 47 [37-57] > 5 years 29 33 [28-38] Inclusion criteria Minimum total score ≥ 6 17 35 [29-40] Minimum total score < 6 22 35 [29-41] Endoscopy subscore for inclusion ≥2 21 34 [30-39] ≥1 5 46 [31-61] Not stated 17 29 [21-39] Bleeding subscore for inclusion Yes 8 38 [30-47] No/not stated 35 32 [27-36] Duration of follow-up ≤ 8 weeks 36 33 [28-39] > 8weeks 7 33 [27-40] Number of follow-up visits ≤3 17 32 [23-45] >3 25 34 [30-38] Publication date Before 2005 15 33 [23-44] After 2005 28 33 [29-37] Time point to measure remission ≤ 6 weeks 16 31 [22-42] > 6weeks 20 35 [30-39] Improvement in endoscopy subscore required for definition Yes 19 32 [27-37] No 24 35 [28-43] Improvement in bleeding subscore required for definition Yes 9 30 [21-39] No 34 34 [29-39] CI, confidence interval.

I2 p-value

Trials N

Pooled rate [95% CI]

< 0.001

40

12 [9-15]

< 0.001

< 0.001 < 0.001 0.06

13 24 3

11 [6-19] 12 [9-16] 6 [2-16]

< 0.001 < 0.001 0.7

< 0.001 0.021

30 10

11 [8-15] 13 [8-22]

< 0.001 < 0.001

< 0.001 < 0.001 0.67

21 15 4

11 [8-15] 12 [7-18] 14 [3-45]

< 0.001 < 0.001 < 0.001

1.00 < 0.001 0.037 < 0.001 0.264

2 9 4 22 3

5 [2-11] 18 [12-24] 10 [2-41] 12 [9-15] 7 [3-18]

0.166 0.005 < 0.001 < 0.001 0.142

< 0.001 < 0.001 < 0.001 0.032

5 15 13 7

18 [9-31] 11 [6-18] 13 [09-18] 8 [6-10]

0.044 < 0.001 < 0.003 0.49

< 0.001 < 0.001

16 24

0.05 < 0.001

8 28

20 [16-25] 11 [8-15]

0.300 < 0.001

< 0.001 < 0.001

18 18

13 [9-19] 12 [9-17]

< 0.001 < 0.001

< 0.001 0.02 < 0.001

22 4 13

12 [9-16] 25 [11-48] 7 [5-10]

< 0.001 < 0.001 0.370

< 0.001 < 0.001

8 32

18 [12-25] 10 [8-14]

0.002 < 0.001

< 0.001 0.064

32 8

11 [9-14] 13 [9-16]

< 0.001 < 0.001

< 0.001 < 0.001

12 24

11 [7-19] 12 [9-16]

< 0.001 < 0.001

< 0.001 < 0.001

12 28

14 [7-23] 11 [9-14]

< 0.001 < 0.001

< 0.001 < 0.001

18 20

11 [7-17] 11 [8-15]

< 0.001 < 0.001

< 0.001 < 0.001

20 20

0.10 [7-14] 0.14 [9-21]

< 0.001 < 0.001

< 0.001 < 0.001

9 31

10 [7-17] 0.12 [9-17]

14 [10-20] 11 [8-15]

I2 p-value

< 0.001 < 0.001

< 0.001 < 0.001

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Table 2.  Univariable meta-regression analysis of factors contributing to placebo response and remission rates in induction trials. Study characteristic

Trial setting Multicentre single-country Multicentre, multinational Single centre Trial design Stand-alone induction vs induction and maintenance trial First author country North America Europe Other Class of drug Corticosteroid Aminosalicylate Immunosuppressant Biological Other Route of administration Topical Oral Intravenous Subcutaneous Disease severity at inclusion Moderate-severe vs mild-moderate Disease duration before enrolment > 5 years vs ≤ 5 years Inclusion criteria Minimum entry score < 6 vs minimum entry score ≥ 6 Endoscopy subscore for entry ≥2 ≥1 Not stated Bleeding subscore for entry [No/not stated vs Yes] Duration of follow-up > 8 weeks vs ≤8 weeks Number of follow-up visits > 3 vs ≤ 3 Publication date After 2005 vs before 2005 Improvement in endoscopy subscore required for definition No vs Yes Time point to measure response > 6 weeks vs ≤ 6 weeks Improvement in bleeding subscore required for definition No vs Yes Number of follow-up visits [per 1-visit increment] Duration of follow-up [per 1-week increment] Screening visits Yes vs No Number of trial centres per 1-centre increment Publication year per 1=year increment Extensive disease/pancolitis ≥ 30% vs < 30% Concurrent steroid Yes vs No

Response

Remission

Odds ratio [95% CI]

p-Value

Odds ratio [95% CI]

p-Value

1.0 1.59 [1.01-2.51] 0.80 [0.30-2.12]

0.047 0.667

1.0 1.17 [0.58-2.34] 0.57 [0.12-2.76]

0.664 0.488

0.75 [0.48-1.16]

0.193

1.26 [0.67-2.38]

0.475

1.0 1.30 [0.89-1.90] 0.28 [0.09-0.86]

0.165 0.026

1.0 1.07 [0.58-1.98] 1.90 [0.68-5.31]

0.83 0.22

1.0 1.57 [0.66-3.70] 0.84 [0.26-2.70] 1.83 [0.81-4.16] 1.69 [0.64-4.48]

0.306 0.766 0.147 0.292

1.0 3.83 [1.16-12.62] 3.94 [0.89-17.38] 2.49 [0.80-7.72] 1.47 [0.32-6.69]

0.027 0.071 0.115 0.618

1.0 0.66 [0.33-1.03] 0.89 [0.49-1.62] 0.81 [0.42-1.59]

0.065 0.710 0.550

1.0 0.66 [0.26-1.68] 0.70 [0.27-1.85] 0.39 [0.13-1.14]

0.382 0.477 0.086

1.10 [0.75-1.62]

0.624

1.06 [0.59-1.92]

0.847

0.54 [0.32–0.92]

0.02

0.60 [0.30-1.23]

0.17

1.02 [0.71-1.47]

0.888

0.89 [0.49-1.62]

0.712

1.0 1.65 [0.93-2.94] 0.77 [0.52-1.13]

0.086 0.178

1.0 2.44 [1.16-5.15] 0.53 [0.29-0.98]

0.019 0.042

0.74 [0.47-1.15]

0.181

0.58 [0.30-1.11]

0.102

0.93 [0.56-1.55]

0.79

1.43 [0.70-2.92]

0.321

1.04 [0.69-1.57] 0.99 [0.65-1.50]

0.8310 0.9468

1.08 [0.55-2.12] 0.72 [0.38-1.35]

0.8236 0.3047

1.19 [0.80-1.75]

0.3870

1.54 [0.87-2.70]

0.1332

1.11 [0.72-1.69]

0.6338

-

-

1.21 [0.76-1.92]

0.4123

0.86 [0.44-1.67]

0.655

1.05 [0.94-1.17]

0.412

1.13 [0.99-1.30]

0.071

1.02 [0.97-1.06]

0.528

1.05 [1.00-1.09]

0.039

1.12 [0.75-0.66]

0.6

0.95 [0.53-1.72]

0.9

1.00 [1.00-1.03]

0.728

1.00 [0.99-1.00]

0.304

1.02 [0.99-1.04]

0.172

0.99 [0.95-1.04]

0.778

1.01 [0.69-1.47]

0.969

1.23 [0.64-2.36]

0.532

0.88 [0.59-1.32]

0.539

1.13 [0.63-2.05]

0.683

Placebo Rates in Ulcerative Colitis Trials

615

Table 2.  Continued Study characteristic

Concurrent immunomodulator Yes vs No Ratio of active drug Placebo > 1 vs ≤ 1 Primary time point to measure endpoint [per 1-week increment]

Response

Remission

Odds ratio [95% CI]

p-Value

Odds ratio [95% CI]

0.79 [0.53-1.16]

0.222

1.18 [0.66-2.10]

1.01 [0.68-1.50]

0.972

0.91 [0.49-1.67]

0.757

1.00 [0.91-1.10]

0.955

1.01 [0.89-1.16]

0.844

p-Value 0.575

CI, confidence interval.

3.8 Publication bias The regression test for funnel plot asymmetry demonstrated that the risk of publication bias was significant [z  =  -3.40, p  8 weeks. The degree of heterogeneity is perhaps surprising given that we refined our eligibility criteria to only include trials that used the UCDAI score, and the outcome definitions for response and remission were broadly similar in the majority of studies. This serves to highlight that many other factors contribute to heterogeneity including demographics, patterns of disease, timing of outcome evaluation, methods of outcome evaluation, and inter-observer variation in outcome evaluation to which endoscopic evaluation is particularly prone.45 Our findings can be compared with those of Su and colleagues who evaluated trials performed before 2005. The current study included 30 RCTs that were published after 2005 and only evaluated trials that used the UCDAI as an outcome measure [51 trials vs 12 in Su et al.].5 Our rationale for using the latter criterion was to focus on trials that used an outcome measure relevant to modern drug development in distinction from those that included indices that are no longer used. Second, we investigated the pooled remission and response rates for induction and maintenance trials separately, which provides new data to inform these separate phases of trial design. Third, we formally assessed the methodological quality of the included trials as well as the possibility of publication bias. Despite this, the findings of the two reviews are broadly similar. Our review has some limitations. First, there were insufficient trials available to evaluate the effect of study-level characteristics of placebo rates for maintenance studies. Second, only one of the trials included utilised central reading of endoscopy,45 so we were unable to evaluate the independent impact of this methodology on placebo rates. Third, there was evidence of statistically significant heterogeneity when data were pooled. Finally, it is important to recognise that despite the detailed analyses we performed using pooled data, the optimum method to investigate the influence of specific patient characteristics on placebo rates is through use of patient-level data. In conclusion, objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers through study follow-up visits increased placebo rates. These findings have important implications for design and conduct of future

clinical trials in UC, in order to maximise assay sensitivity and improve trial efficiency.

Funding No external funding for this work was received. VJ: salary is part funded by the UK National Institute for Health Research. PSD is supported by the National Institute of Diabetes and Digestive and Kidney Diseases [Grant 5T32DK007202].

Conflict of Interest VJ: has received scientific advisory board fees from AbbVie. GYZ is an employee of Robarts Clinical Trials which was the research organisation that conducted this study. MHM is an employee of Robarts Clinical Trials which was the research organisation that conducted this study. RK has received honoraria from Takeda Pharma and consulting fees from AbbVie. LMS is an employee of Robarts Clinical Trials which was the research organisation that conducted this study. MKV is an employee of Robarts Clinical Trials which was the research organisation that conducted this study. ST has received grant support from AbbVie, IOIBD, Lilly, Norman Collison Foundation [all to Institution]; advisory board fees [all suspended Q1 2012-14 as President of ECCO] from AbbVie, Asahi, AstraZeneca, Boehringer Ingelheim, Celgene, Cosmo, ChemoCentryx, Ferring, FPRT Bio, Genentech/Roche, GSK, Lilly, Novartis, Novo Nordisk, Pfizer, Proximagen, Receptos, SigmoidPharma, Synthon,Takeda, Topivert, Trino Therapeutics with Wellcome Trust, UCB Pharma, Vertex, VHSquared, Vifor, Warner Chilcott. GDH has received consulting fees from Abbott/ Abbvie, ActoGeniX NV, Amgen, AM-Pharma BV, Boehringer-Ingelheim, ChemoCentryx, Centocor/Jansen Biologics, Cosmo Technologies, Elan/Biogen, EnGene Inc, Ferring Pharmaceuticals, Gilead Sciences, Given Imaging, GSK, Merck Research Laboratories, Merck Serono, Millenium Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, PDL Biopharma, Pfizer, Receptos, Salix Pharmaceuticals, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Teva Pharmaceuticals, Tillotts Pharma AG, UCB Pharma; research grants from Abbvie, GSK, Falk, Janssen, Merck, Given Imaging; payments for lectures/speakers’ bureaux from Abbvie, Jansen, Merck, Takeda, UCB, Shire. BGL is a consultant for Prometheus Laboratories and Santarus; has participated on speakers’ bureau for Salix; and is an employee of Robarts Clinical Trials which was the research organisation that conducted this study. WJS has received consulting fees from Abbott, ActoGeniX NV, AGI Therapeutics Inc., Alba Therapeutics Corp., Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys Inc., Atlantic Healthcare Ltd, Aptalis, BioBalance Corp., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, EnGene Inc, Eli Lilly, Enteromedics, Exagen Diagnostics Inc., Ferring Pharmaceuticals, Flexio Therapeutics Inc., Funxional Therapeutics Ltd, Genzyme Corp., Gilead Sciences, Given Imaging, GSK, Human Genome Sciences, Ironwood Pharmaceuticals, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp., Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Millenium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics Inc., PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Ltd, Purgenesis Technologies Inc., Relypsa Inc., Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma Ltd, Sirtris Pharmaceuticals, SLA Pharma UK Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Ltd, Warner Chilcott UK Ltd, and Wyeth; research grants from Abbott, Bristol-Myers Squibb, Genentech, GSK, Janssen, Milennium Pharmaceuticals, Novartis, Pfizer, Procter and Gamble, Shire Pharmaceuticals, and UCB Pharma; payments for lectures/ speakers’ bureaux from Abbott, Bristol-Myers Squibb, and Janssen; and holds stock/stock options in Enteromedics. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, Abbott Labs, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc.,

Placebo Rates in Ulcerative Colitis Trials Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, Abbott Labs, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc., Sigmoid Pharma; speakers’ bureau fees from UCB, Abbott, J&J/Janssen.

Author Contributions Guarantors of the article: VJ, BGF. Development of study concept and design: VJ, BGL, WJS, BGF. Study supervision: VJ, GYZ, WJS, BGF, CP, JKM. Acquisition, analysis, and interpretation of the data: VJ, TA, MA, MA, TA, NA, SB, TC, PSD, MG, DH, AK, EM, ST, GD, BGL, WJS, BGF. Statistical analysis: GYZ. Drafting of the manuscript: VJ, GYZ, CP, JKM, BGF. Critical revision of the manuscript for important intellectual content: VJ, GYZ, CP, JKM, RK, MHM, MKV, TA, MA, MA, TA, NA, SB, TC, PSD, MG, DH, AK, EM, ST, GD, BGL, WJS, BGF. All authors approved the final version of the manuscript including the authorship list.

Supplementary Data Supplementary data are available at ECCO-JCC online.

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Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates...
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